Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• The RAS gene family is frequently mutated in human cancers.
• Developing compounds that bind to mutant RAS and inhibit protein-protein interactions is a critical goal in cancer research.

Purpose of the Study:

• To identify and develop novel RAS-binding compounds.
• To create potent inhibitors of RAS-effector interactions by combining chemical series.

Main Methods:

• Refined crystallization conditions for KRASQ61H.
• Screened a protein-protein interaction-focused compound library using surface plasmon resonance.
• Developed fused compounds by combining structural elements from different RAS-binding series.

Main Results:

• Identified two RAS-binding compounds (PPIN-1 and PPIN-2).
• Developed fused compounds that inhibit RAS-effector interactions with increased potency.
• Demonstrated a strategy for creating RAS-binding small molecules by crossing chemical series.

Conclusions:

• Novel RAS-binding compounds were successfully developed.
• Fused compounds represent a promising new class of RAS-protein-protein inhibitors.
• Combining chemical series is an effective strategy for developing targeted cancer therapeutics.